Coinfection

AASLD 2013: Sofosbuvir + Ribavirin Produces Sustained Response in 76% of GT 1 HIV/HCV Coinfected Patients

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An interferon-free regimen of sofosbuvir plus ribavirin taken for 24 weeks cured three-quarters of previously untreated HIV positive people coinfected with hepatitis C virus (HCV) genotype 1, while 12 weeks of treatment cured 88% and 67% of those with genotypes 2 or 3, according to findings from the Phase 3 PHOTON-1 study presented this week at the 64th AASLD Liver Meeting in Washington, DC.

People coinfected with HIV and HCV experience more rapid liver disease progression and do not respond as well to interferon-based hepatitis C treatment as patients with HCV alone. Direct-acting antivirals have the potential to dramatically improve response rates for coinfected individuals, but this population may be more prone to adverse events and faces the issue of drug-drug interactions with antiretroviral therapy (ART).

Mark Sulkowski from Johns Hopkins Medical Center and colleagues conducted a study to evaluate the safety and efficacy of Gilead Sciences' sofosbuvir (formerly GS-7977) administered with ribavirin to coinfected patients.

Sofosbuvir is a potent nucleotide HCV NS5B polymerase inhibitor with activity against HCV genotypes 1 through 6 and a high genetic barrier to resistance. Unlike some HCV protease inhibitors, it does not affect CYP3A4 liver enzyme metabolism and has demonstrated no significant interactions with many widely used antiretroviral drugs.

Last month a U.S. Food and Drug Administration advisory committee recommended approval of sofosbuvir both as an add-on to pegylated interferon/ribavirin for people with HCV genotype 1 and as part of a dual regimen with ribavirin for people with genotypes 2 or 3. This all-oral regimen was previously found to produce a sustained virological response (SVR) rate as high as 97% for HIV-negative genotype 2 patients. However, sofosbuvir's initial indication is not expected to include HIV/HCV coinfection.

The open-label PHOTON-1 trial enrolled 114 coinfected U.S. patients with HCV genotype 1 who had not been previously treated for hepatitis C. They received 400 mg once-daily sofosbuvir plus 1000-1200 mg weight-based ribavirin for 24 weeks and were followed for 12 weeks after completion of therapy to determine SVR12.

The study also included 109 people with genotypes 2 or 3. Treatment-naive patients -- 26 with genotype 2 and 42 with genotype 3 -- received the same regimen for 12 weeks and were again followed for 12 weeks post-treatment. The remainder are treatment-experienced and received sofosbuvir plus ribavirin for 24 weeks; the latter group is still in treatment or follow-up and not included in Sulkowski's report.

Across all genotypes, most participants (81%) were men and the mean age was about 49 years. One-third of genotype 1 patients, 23% of genotype 2 patients, and only 5% of genotype 3 patients were black, a population that responds less well to interferon-based therapy; 27%, 39%, and 36%, respectively, had the favorable IL28B CC gene variant associated with good interferon response. Most genotype 1 patients had harder-to-treat subtype 1a. In the genotype 1 and 2 groups, 4% had compensated cirrhosis, rising to 14% in the genotype 3 group.

Participants had well-controlled HIV disease. More than 90% were on antiretroviral treatment and the mean CD4 T-cell count was above 600 cells/mm3. Approximately one-third used ART regimens containing efavirenz (Sustiva), followed by the boosted HIV protease inhibitors atazanavir (Reyataz) or darunavir (Prezista), and the integrase inhibitor raltegravir (Isentress), all in combination with tenofovir/emtricitabine (the drugs in Truvada).

Results

  • About 90% of participants across genotype groups completed treatment.
  • Rapid virological response (RVR) rates at week 4 after starting therapy were 96% for genotype 1 and 2 patients, and 100% for those with genotype 3.
  • At the end of treatment 100%, 96%, and 98%, respectively, had undetectable HCV viral load.
  • After finishing therapy, however, a number of people experienced treatment failure, resulting in SVR12 rates of 76% for genotype 1, 88% for genotype 2, and 67% for genotype 3 -- substantially higher than cure rates seen in historical studies of pegylated interferon plus ribavirin.
  • Relapse rates were 22% for genotype 1 and 29% for genotype 3 patients, but no one with genotype 2 relapsed; most relapses occurred within 4 weeks after finishing treatment.
  • 2 individuals experienced HCV viral breakthrough while on treatment (1 each in the genotype 1 and 2 groups), both of whom were found to be non-adherent.
  • No resistance mutations (including S282T) were detected in people with virological failure.
  • Black race -- but not IL28B status -- and failure to complete therapy were the only factors that independently predicted non-response; cirrhosis and HCV subtype 1b (contrary to most studies) were also associated with lower response, but numbers were small and differences did not reach statistical significance.
  • Sofosbuvir plus ribavirin was generally safe and well-tolerated.
  • Across all genotypes, serious adverse events (7% in both the 12- and 24-week treatment arms) and grade 3-4 laboratory abnormalities (10% and 13%) were uncommon; 4% and 3%, respectively, discontinued treatment early due to adverse events.
  • The most common side effects were fatigue, insomnia, headache, and nausea, occurring with similar frequency in the 12- and 24-week arms.
  • Anemia was reported in 10% and 19%, respectively, and elevated bilirubin was seen among people taking atazanavir.
  • Looking at HIV disease progression, 2 patients had HIV viral breakthrough and both were found to be non-adherent to ART; absolute CD4 counts fell (a known effect of ribavirin) but percentages remained the same.

"The interferon-free regimen of sofosbuvir + ribavirin resulted in high SVR12 rates in HCV treatment-naive, HIV-infected patients with genotype 1, 2 and 3 co-infection," the researchers concluded. "SVR12 rates were similar to those observed in patients with HCV monoinfection."

This finding supports the growing awareness that HCV genotypes 2 and 3 should not be classified together as "easier to treat," as in fact genotype 3 is more difficult.

"In this study, sofosbuvir-based all-oral therapy achieved high SVR rates in a hard-to-treat patient population," PHOTON-1 co-investigator Douglas Dieterich from Mt. Sinai School of Medicine stated in a press release issued by Gilead. "This regimen may have the potential to help us overcome the clinical challenge of treating HCV/HIV co-infection."

However, in a comment via Twitter during the session, Jean-Michel Pawlotsky, from the French National Reference Center for Viral Hepatitis B, C and Delta, characterized the PHOTON-1 response rates as "disappointing" -- compared with the 90%+ SVR rates obtained for HCV monoinfected people in several recent studies -- and suggested that an additional direct-acting antiviral may be needed for coinfected patients.

11/5/13

Reference

MS Sulkowski, M Rodriguez-Torres, JP Lalezari, et al. All-Oral Therapy With Sofosbuvir Plus Ribavirin For the Treatment of HCV Genotype 1, 2, and 3 Infection in Patients Co-infected With HIV (PHOTON-1). 64th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD 2013). Washington, DC, November 1-5, 2013. Abstract212.

Other Source

Gilead Sciences. Gilead Announces Phase 3 Results for an All-Oral, Sofosbuvir-Based Regimen for the Treatment of Hepatitis C in Patients Co-Infected with HIV. Press release. November 2, 2013.